The long-term objectives of this revised proposal are to devise novel nutritional approaches for colon cancer prevention. The proposed study involves non-human primates and has been designed to provide data to directly support subsequent clinical studies on soy isoflavones in humans. Marked differences in the incidence of colon cancer between Western societies (high incidence) and Asian countries like Japan (low incidence) are attributed in large part to differences in their respective diets and may be related to the high consumption of soy protein in Asian countries. Soy protein is rich in heterocyclic phenolic compounds called isoflavones, which are known to exert potent anticancer properties both in vivo and in vitro. The primary specific aim is to determine if soy isoflavones at dietary levels achievable by the average American reduce colon cell proliferation, an accepted intermediate marker of colon cancer risk, in cynomologus monkeys fed a high-fat diet. Secondary aims are to determine whether soy isoflavones: 1) reduce synthesis of prostaglandin E2 in colon, 2) increase apoptosis in colon crypt epithelium, 3) reduce methylation of the estrogen receptor gene, and 4) reduce fecal bile acid secretion. A western style, high-fat diet containing soy isoflavones, or a control diet, will be fed to surgically postmenopausal female monkeys. Colon biopsies will be collected at baseline and after approximately 4 and 8 months of treatment. All monkeys will be euthanized after 12 months of treatment, and additional colon samples will be collected for analysis, as will mammary gland and uteri. Cell proliferation will be assessed by immunostaining for proliferating cell nuclear antigen, and proliferating cells will be quantified by detailed histomorphometric analysis. Additional measurements include Prostaglandins, apoptosis, estrogen receptor gene methylation, and fecal bile acids. Treatment effects will be determined using repeated measures analysis of covariance and ANCOVA techniques. These studies will provide information on the potential beneficial effects of isoflavones on cell proliferation in colon, as well as other related biological risk factors for colon cancer, in a unique monkey model. If positive, these data will strongly support future studies in humans.
